CCR2 is a member of the GPCR (G-protein coupled receptor) family of receptors, as are all known chemokine receptors and are expressed by monocytes and memory T-lymphocytes. The CCR2 signaling cascade involves activation of heterotrimeric G proteins, phospholipases (and notably PLCβ2), protein kinases like PKC and PI-3K and cytosolic elevation of calcium.
Chemoattractant cytokines (i.e., chemokines) are relatively small proteins (8-10 kD) which trigger the migration of cells. The chemokine family is divided into four subfamilies based on the number and space of amino acid residues between the first and second highly-conserved cysteines.
The chemokine termed CCL2 (also known as Monocyte chemotactic protein-1 or MCP-1) is a member of the CC chemokine subfamily (wherein CC represents the subfamily having adjacent first and second cysteines) and binds to the cell-surface chemokine receptor 2 (CCR2). CCL2 is a potent chemotactic factor which, after binding to CCR2, mediates monocyte and lymphocyte migration (i.e., chemotaxis) toward a site of inflammation. CCL2 is produced by a wide variety of cell types in response to inflammatory conditions, such as cardiac muscle cells, blood vessel endothelial cells, fibroblasts, chondrocytes, smooth muscle cells, mesangial cells, alveolar cells, T-lymphocytes, macrophages, neurons and the like.
After monocytes enter the inflammatory tissue and differentiate into macrophages, monocyte differentiation provides a secondary source of several proinflammatory modulators, including tumor necrosis factor-alpha (TNFα) interleukin-1 (IL-1), CXCL-8 (a member of the CXC chemokine subfamily, wherein CXC represents one amino acid residue between the first and second cysteines), IL-12, arachidonic acid metabolites (e.g., PGE2 and LTB4), oxygen-derived free radicals, matrix metalloproteinases and complement components.
Animal model studies of chronic inflammatory diseases have demonstrated that inhibition of binding between CCL2 and CCR2 by an antagonist suppresses the inflammatory response. The interaction between CCL2 and CCR2 has been implicated (see Rollins B J, Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease, Mol. Med. Today, 1996, 2:198; and Dawson J, et al., Targeting monocyte chemoattractant protein-1 signaling in disease, Expert Opin. Ther. Targets, 2003 Feb. 7(1):35-48) in inflammatory disease pathologies such as uveitis, atherosclerosis, rheumatoid arthritis, multiple sclerosis, Crohn's Disease, nephritis, organ allograft rejection, fibroid lung, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis, sarcoidosis, invasive staphylococcia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma, periodontal diseases, periodonitis, gingivitis, gum disease, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart failure, angiostenosis, restenosis, reperfusion disorders, glomerulonephritis, solid tumors and cancers, chronic lymphocytic leukemia, chronic myelocytic leukemia, multiple myeloma, malignant myeloma, Hodgkin's disease, and carcinomas of the bladder, breast, cervix, colon, lung, prostate, or stomach.
Monocyte migration is inhibited by CCL2 antagonists (either antibodies or soluble, inactive fragments of MCP-1) which have been shown to inhibit the development of arthritis, asthma, and uveitis. Both CCL2 and CCR2 knockout (KO) mice have demonstrated that monocyte infiltration into inflammatory lesions is significantly decreased. In addition, such KO mice are resistant to the development of experimental allergic encephalomyelitis (EAE, a model of human multiple sclerosis), cockroach allergen-induced asthma, atherosclerosis, and uveitis. Rheumatoid arthritis and Crohn's Disease patients have improved during treatment with TNF-α antagonists (e.g., monoclonal antibodies and soluble receptors) at dose levels correlated with decreases in CCL2 expression and the number of infiltrating macrophages.
Thus, CCR2 antagonists represent a new class of important therapeutic agents. So far efforts have focused on developing either chemicals (see e.g. Brodmerkel et al, J. Immunol, 2005, 175:5370-7378) or anti-CCR2 antibodies (see e.g. U.S. Pat. No. 7,566,539).
There remains a need for specific CCR2 antagonist small molecules for preventing, treating or ameliorating a CCR2 mediated disorder.